Mouse, non-human primate (NHP) and human Tfh cells share phenotypic, functional and molecular programs which are regulated by local signals and spatiotemporal factors. Chronic HIV/SIV infection results in accumulation of Tfh, germinal center (GC) B cells and circulating virus-specific immunoglobulins in some subjects. However, most HIV/SIV infected subjects do not mount broadly neutralizing antibodies, pointing to functional defects in Tfh cells in chronic HIV/SIV infection. The susceptibility of particular CD4 T cells populations to HIV/SIV infection within lymph nodes notably impacts upon the dynamics of Tfh-GC B cell interactions. Some circulating CD4 T cells share certain characteristics with Tfh cells, however their direct origin from GC Tfh cells is not clear. There are many ways in which HIV and SIV influence the complex signals and mechanisms regulating the development of Tfh cells and their interactions with GC B cells. Understanding the biology of Tfh cells will be necessary to appropriately recruit these cells during vaccination with the goal of stimulating a more broad and potent neutralizing antibody response.